According to the US Department of Veterans Affairs, heart failure (HF) and associated complications are one of the main reasons for hospital readmissions and death in the Veterans Health Care System. In fact, above 40 years of age, the lifetime risk of developing HF is one in 5, and readmissions occur within 30 days of discharge in 20% of patients older than 65 in the Medicare population and the Veterans Health Care System. Together, these healthcare systems incurred nearly $37.2 billions for HF care in 2009. A substantial number of patients develop severe LVH secondary to pressure overload (e.g., hypertension, aortic valve stenosis), and experience episodic severe congestive HF, hospitalization, and increased mortality. Pressure overload-induced left ventricular hypertrophy and transition to heart failure involves activation of both inflammatory and innate immune pathways, with the sustained activation of Nuclear factor kappa B (NF-?B) and Activator Protein 1 (AP-1) playing a key role in their pathogenesis. Our studies, both published and preliminary, clearly indicate that the cytoplasmic adapter molecule TRAF3IP2 (TRAF3 Interacting Protein 2) plays a causal role in the pathogenesis of pressure overload-induced myocardial hypertrophy, fibrosis and dysfunction in a pre-clinical mouse model. Our pilot experiments also demonstrate TRAF3IP2 expression is increased in both hypertrophic and failing human hearts. Based on these critical findings, our central hypothesis is that TRAF3IP2 plays a pivotal role in pressure overload-induced adverse cardiac remodeling and heart failure development by inducing the activation of critical signaling intermediates like I?B kinase (IKK)/NF-?B and c-Jun N-terminal kinase (JNK)/AP-1, increased expression and secretion of pro-inflammatory and pro-fibrotic mediators, and excessive production and deposition of altered extracellular matrix, resulting ultimately in adverse cardiac remodeling and contractile dysfunction. While our long-term goals are to understand the molecular mechanisms involved in the pathophysiology of myocardial hypertrophy and its transition to heart failure, and to identify novel therapeutic target(s) for intervention and treatment, our immediate goals are to determine the etiological role of TRAF3IP2 in the pathogenesis of pressure overload-induced adverse cardiac remodeling and heart failure development, and to develop an interventional strategy to target its expression in the heart. To test our central hypothesis, three specific aims are proposed: In Specific Aim 1, we will define the causal role of TRAF3IP2 in pressure overload-induced myocardial hypertrophy, fibrosis and failure using inducible cardiomyocyte-specific TRAF3IP2 knockout and overexpressor mice. In Specific Aim 2, we will delineate the causal role of TRAF3IP2 in pressure overload-induced LVH, fibrosis and failure using fibroblast-specific TRAF3IP2 knockout mice. In Specific Aim 3, we will establish the effectiveness of UTMD (ultrasound-targeted microbubble destruction)-mediated silencing of TRAF3IP2 to attenuate pressure overload-induced LVH, fibrosis and failure in wild type mice. These novel and innovative studies utilizing cell type-specific gene-altered mouse models and UTMD- mediated preventative and curative interventional approach, as well as state-of-the art techniques (functional, biochemical, histological, and molecular analyses) will evaluate TRAF3IP2 as a central causative factor, and thus a potential therapeutic target in pressure overload-induced adverse cardiac remodeling and heart failure development.